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Clinical Trial Results:
A Phase III, Randomised, Double Blind, Placebo Controlled and Open Label Phase, Multicentre Study to Investigate the Efficacy and Safety of BTX-A-HAC NG in the Treatment of Moderate to Severe Glabellar Lines, and Assess the Long Term Efficacy and Safety of BTX-A-HAC NG Following Repeated Treatments in this Indication.

Summary
EudraCT number	2014-003841-86
Trial protocol	DE GB
Global end of trial date	02 Dec 2016

Results information
Results version number	v1(current)
This version publication date	19 Aug 2018
First version publication date	19 Aug 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

Y-52-52120-214

ISRCTN number

US NCT number

NCT02493946

WHO universal trial number (UTN)

Sponsor organisation name

Ipsen Innovation

Sponsor organisation address

65 quai Georges Gorse, Boulogne-Billancourt, France, 92100

Public contact

Medical Director, Neurology, Ipsen Innovation, clinical.trials@ipsen.com

Scientific contact

Medical Director, Neurology, Ipsen Innovation, clinical.trials@ipsen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Dec 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Oct 2015

Global end of trial reached?

Yes

Global end of trial date

02 Dec 2016

Was the trial ended prematurely?

Main objective of the trial

To assess short-term efficacy and safety of a single treatment of Clostridium botulinum toxin type A Haemagglutinin Complex (BTX-A-HAC) solution 50 Units (U) over placebo for the improvement in the appearance of glabellar lines and to assess the long term (LT) safety and efficacy of BTX-A-HAC solution 50 U after repeated injections. The primary objective was to demonstrate the superiority of BTX-A-HAC solution 50 U (0.25 milliltre [mL]) over placebo as measured by the Investigator's live assessment (ILA) of the appearance of the subject's glabellar lines at maximum frown on Day 29 of the double blind (DB) period.

Protection of trial subjects

The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Council for Harmonisation Consolidated Guideline on Good Clinical Practice and Food and Drug Administration (FDA), 21 CFR Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerized Systems Used in Clinical Trials.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 24

Country: Number of subjects enrolled

France: 163

Country: Number of subjects enrolled

Germany: 413

Worldwide total number of subjects

600

EEA total number of subjects

600

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

588

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects with moderate or severe glabellar lines were enrolled in 24 sites in France, Germany and the United Kingdom from 23 April 2015. The study was completed in December 2016.

Screening details

605 subjects were screened. 192 were screened for the DB period; 2 were screen failures and 190 were randomised to treatment or placebo. 413 additional subjects were screened for the open label (OL) period, referred to as de novo subjects; 3 were screen failures and 410 received at least one treatment cycle.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Carer, Subject

Are arms mutually exclusive

BTX-A-HAC Solution 50 U - DB Period

Arm description

During the DB period, subjects were randomised to receive a single treatment of BTX-A-HAC solution 50 U. 50 U (0.25 mL) BTX-A-HAC was administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive further BTX-A-HAC treatment.

Arm type

Experimental

Investigational medicinal product name

BTX-A-HAC Solution 50 U

Investigational medicinal product code

Other name

Botulinum Toxin Type A, BTX-A-HAC NG

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

In each treatment cycle subjects received a single treatment with 50 U (0.25 mL) BTX-A-HAC administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region.

Placebo - DB Period

Arm description

During the DB period, subjects were randomised to receive a single treatment of placebo. 0.25 mL placebo was administered as five injections of 0.05 mL each into one of five predefined sites across the glabellar region. Subjects who completed the DB treatment (Cycle 1) were eligible to continue to the OL period to receive BTX-A-HAC treatment.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

In each treatment cycle subjects received a single treatment with 0.25 mL placebo administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region. Placebo was provided as a liquid identical to BTX-A-HAC solution, containing only the excipients of BTX-A-HAC solution.

BTX-A-HAC Solution 50 U - LT Analyses

Arm description

Eligible subjects who completed the DB Cycle 1 treatment were able to receive further treatment in the OL period (OL Cycles 2 to 5). Additional BTX-naïve (de novo) subjects were enrolled into the OL period to receive treatment with BTX-A-HAC during OL Cycle 1, and if eligible for retreatment de novo subjects received retreatment in OL Cycles 2 to 5. Each treatment cycle included a single treatment with 50 U (0.25 mL) BTX-A-HAC administered as five injections of 10 U (0.05 mL) each into one of five predefined sites across the glabellar region, and treatments were separated by at least 12 weeks.

Arm type

Experimental

Investigational medicinal product name

BTX-A-HAC Solution 50 U

Investigational medicinal product code

Other name

Botulinum Toxin Type A, BTX-A-HAC NG

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Number of subjects in period 1	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period	BTX-A-HAC Solution 50 U - LT Analyses
Started	126	64	595
Completed	118	59	509
Not completed	8	5	86
Consent withdrawn by subject	8	5	74
Site error	-	-	1
Adverse event, non-fatal	-	-	4
Pregnancy	-	-	3
Investigator decision - non-compliance	-	-	2
Lost to follow-up	-	-	1
Investigator decision - non-availability	-	-	1

Baseline characteristics

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Reporting group title

BTX-A-HAC Solution 50 U - DB Period

Reporting group description

Reporting group title

Placebo - DB Period

Reporting group description

Reporting group title

BTX-A-HAC Solution 50 U - LT Analyses

Reporting group description

Reporting group values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period	BTX-A-HAC Solution 50 U - LT Analyses	Total
Number of subjects	126	64	595	600
Age categorical
Units: Subjects
In Utero	0	0	0	0
Preterm newborn-gestational age < 37 wk	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days - 23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
From 18 - 64 years	123	64	586	588
From 65 - 84 years	3	0	9	12
Over 85 years	0	0	0	0
Gender categorical
Units: Subjects
Female	115	58	530	533
Male	11	6	65	67
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	1	1
Asian	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	1	0	1	1
White	125	64	589	594
More than one race	0	0	0	0
Unknown or Not Reported	0	0	3	3

End points

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Reporting group title

BTX-A-HAC Solution 50 U - DB Period

Reporting group description

Reporting group title

Placebo - DB Period

Reporting group description

Reporting group title

BTX-A-HAC Solution 50 U - LT Analyses

Reporting group description

Primary: The Percentage of Responders at Day 29 Cycle 1 as Measured by ILA of Glabellar Lines at Maximum Frown: DB Period

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End point title

The Percentage of Responders at Day 29 Cycle 1 as Measured by ILA of Glabellar Lines at Maximum Frown: DB Period ^[1]

End point description

The appearance of glabellar lines at maximum frown was assessed in the DB period at the Day 29 follow-up visit using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The percentage of responders at Day 29 Cycle 1 is presented. Results are presented for the modified intent-to-treat (mITT) population which consisted of all subjects who were randomised, received study treatment (BTX-A-HAC solution or placebo) and completed one post-treatment assessment of the ILA of glabellar lines at maximum frown.

End point type

Primary

End point timeframe

Day 29 (Cycle 1)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	124	61
Units: Percentage of Responders
number (confidence interval 95%)	81.6 (61.3 to 92.5)	0.8 (0.1 to 4.8)

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference against placebo in the percentage of responders.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

80.8

Confidence interval

level

95%

sides

2-sided

lower limit

73.7

upper limit

Notes
[2] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

Secondary: The Percentage of Responders at Each Post-Treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period

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End point title

The Percentage of Responders at Each Post-Treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period ^[3]

End point description

The appearance of glabellar lines at maximum frown was assessed in the DB period at post-treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The percentage of responders is presented at Days 8, 57 and 85. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Days 8, 57 and 85 (Cycle 1).

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Percentage of Responders
number (confidence interval 95%)
Day 8	75.9 (56.7 to 88.3)	0.9 (0.1 to 5.5)
Day 57 (n=122; n=60)	74.7 (51.4 to 89.2)	0.6 (0.1 to 4.0)
Day 85 (n=123; n=59)	55.5 (35.8 to 73.5)	1.8 (0.4 to 8.9)

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

67.1

upper limit

82.8

Notes
[4] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

74.1

Confidence interval

level

95%

sides

2-sided

lower limit

66.2

upper limit

82.1

Notes
[5] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

53.6

Confidence interval

level

95%

sides

2-sided

lower limit

44.2

upper limit

63.1

Notes
[6] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

Secondary: The Percentage of Responders on Day 29 Cycle 1 Who Remained Responders on Days 57 and 85 as Measured by the ILA at Maximum Frown: DB Period

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End point title

The Percentage of Responders on Day 29 Cycle 1 Who Remained Responders on Days 57 and 85 as Measured by the ILA at Maximum Frown: DB Period ^[7]

End point description

The appearance of glabellar lines at maximum frown was assessed in the DB period at post treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The percentage of responders at Day 29 of Cycle 1 who still fulfilled the criteria for a responder at Days 57 and 85 is presented. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Days 29, 57 and 85 (Cycle 1).

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Percentage of Responders
number (confidence interval 95%)
Day 57 (n=106; n=1)	87.7 (81.5 to 94.0)	100.0 (100.0 to 100.0)
Day 85 (n=106; n=1)	63.2 (54.0 to 72.4)	0 (0 to 0)

No statistical analyses for this end point

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period

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End point title

The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period ^[8]

End point description

The appearance of glabellar lines at rest was assessed in the DB period at post treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline (Day 1 Cycle 1). The percentage of responders is presented for Days 8, 29, 57 and 85. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 (Cycle 1).

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Percentage of Responders
number (confidence interval 95%)
Day 8 (n=90; n=42)	69.4 (49.2 to 84.2)	11.4 (3.9 to 29.0)
Day 29 (n=89; n=41)	62.2 (39.0 to 80.9)	5.4 (1.4 to 18.5)
Day 57 (n=87; n=40)	63.1 (35.2 to 84.4)	0.6 (0.0 to 8.2)
Day 85 (n=88; n=39)	49.5 (29.0 to 70.1)	6.8 (1.9 to 22.0)

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

44.5

upper limit

71.6

Notes
[9] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 29 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[10]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

56.8

Confidence interval

level

95%

sides

2-sided

lower limit

44.5

upper limit

Notes
[10] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[11]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

62.5

Confidence interval

level

95%

sides

2-sided

lower limit

52.1

upper limit

72.9

Notes
[11] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[12]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

42.6

Confidence interval

level

95%

sides

2-sided

lower limit

29.5

upper limit

55.7

Notes
[12] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period

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End point title

The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period ^[13]

End point description

The appearance of glabellar lines at maximum frown was assessed using the SSA, a validated 4-point categorical scale of glabellar line severity, in the DB period at post-treatment follow-up visits. A responder was defined as having a severity grade of no wrinkles (Grade 0) or mild wrinkles (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) wrinkles at baseline (Day 1 Cycle 1). Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 (Cycle 1).

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Percentage of Responders
number (confidence interval 95%)
Day 8	63.5 (44.0 to 79.3)	2.3 (0.6 to 9.1)
Day 29 (n=124; n=61)	68.1 (48.4 to 82.9)	2.3 (0.6 to 8.5)
Day 57 (n=122; n=60)	71.2 (51.2 to 85.3)	0.7 (0.1 to 6.8)
Day 85 (n=123; n=60)	34.7 (18.5 to 55.4)	1.7 (0.3 to 8.0)

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[14]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

61.1

Confidence interval

level

95%

sides

2-sided

lower limit

51.9

upper limit

70.3

Notes
[14] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 29 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[15]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

65.8

Confidence interval

level

95%

sides

2-sided

lower limit

56.8

upper limit

74.8

Notes
[15] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[16]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

70.5

Confidence interval

level

95%

sides

2-sided

lower limit

62.2

upper limit

78.8

Notes
[16] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[17]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[17] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: DB Period

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End point title

The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: DB Period ^[18]

End point description

The subject’s level of satisfaction with the appearance of their glabellar lines was assessed in the DB period at post-treatment follow-up visits using a 4-point categorical scale. A responder was defined as having a satisfaction rating of very satisfied (Grade 0) or satisfied (Grade 1) at a given visit and a satisfaction rating of dissatisfied (Grade 2) or very dissatisfied (Grade 3) at baseline (Day 1 Cycle 1). The percentage of responders is presented for Days 8, 29, 57 and 85. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 (Cycle 1).

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Percentage of Responders
number (confidence interval 95%)
Day 8	76.3 (59.3 to 87.6)	8.1 (3.0 to 19.7)
Day 29 (n=124; n=61)	83.1 (67.3 to 92.1)	5.7 (1.9 to 15.7)
Day 57 (n=122; n= 60)	77.9 (60.0 to 89.2)	3.5 (1.0 to 11.9)
Day 85 (n=123; n=60)	51.3 (30.7 to 71.4)	0.3 (0.0 to 4.2)

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[19]

Method

Regression, Linear

Parameter type

Treatment difference

Point estimate

68.2

Confidence interval

level

95%

sides

2-sided

lower limit

58.2

upper limit

78.3

Notes
[19] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 29 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

77.4

Confidence interval

level

95%

sides

2-sided

lower limit

68.6

upper limit

86.2

Notes
[20] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[21]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

74.4

Confidence interval

level

95%

sides

2-sided

lower limit

65.7

upper limit

83.1

Notes
[21] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference against placebo in the percentage of responders at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[22]

Method

Regression, Logistic

Parameter type

Treatment difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

59.9

Notes
[22] - The treatment difference and p-value were obtained from a logistic regression on responders with treatment group, gender, baseline severity score on ILA at maximum frown and centre as fixed variables.

Secondary: The Median Time to Onset of Treatment Response Based on the Subject’s Diary Card: DB Period

Top of page

End point title

The Median Time to Onset of Treatment Response Based on the Subject’s Diary Card: DB Period ^[23]

End point description

Subjects were asked to record their assessment of study treatment response on a diary card on Days 1 to 7 at approximately the same time each day. Subjects were asked to respond ‘yes’ or ‘no’ to the following question: ‘Since being injected have you noticed an improvement in the appearance of your glabellar lines (lines between your eyebrows)?’ The time to onset of response was defined as the first day the subject responded 'yes' to this question. Results are presented for the mITT population.

End point type

Secondary

End point timeframe

Days 1 to 7 (Cycle 1).

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63 ^[24]
Units: Days
median (confidence interval 95%)	2.0 (2.0 to 3.0)	99999999 (99999999 to 99999999)

Notes
[24] - 99999999 indicates value was not calculated due to the small number of responders.

BTX-A-HAC vs Placebo

Statistical analysis description

Treatment difference in median time to onset of treatment response.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[25]

Method

Cox proportional hazard model

Confidence interval

Notes
[25] - The Hazard ratio calculated with centre, gender and ILA baseline severity score as covariates = 15.296.

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: DB Period

Top of page

End point title

Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: DB Period ^[26]

End point description

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the satisfaction with facial appearance overall scale. This consisted of 10 items with 4 possible answers for each: 1 (Very Dissatisfied), 2 (Somewhat Dissatisfied), 3 (Somewhat Satisfied) and 4 (Very Satisfied). The least squares mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (most dissatisfied) to 100 (most satisfied) using a conversion table. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Days 8, 29, 57 and 85 (Cycle 1).

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Scores on a Scale
least squares mean (standard error)
Day 8 (n=123; n=62)	9.4 ( 1.72 )	0.8 ( 1.93 )
Day 29 (n=123; n=60)	8.1 ( 1.90 )	-3.0 ( 2.12 )
Day 57 (n=121; n=59)	11.2 ( 1.83 )	0.7 ( 2.03 )
Day 85 (n=122; n=59)	4.7 ( 1.91 )	-5.0 ( 2.15 )

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[27]

Method

General linear model

Parameter type

Treatment difference

Point estimate

8.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.2

upper limit

Notes
[27] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariates.

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 29 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[28]

Method

General linear model

Parameter type

Treatment difference

Point estimate

11.1

Confidence interval

level

95%

sides

2-sided

lower limit

7.4

upper limit

14.8

Notes
[28] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariates.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[29]

Method

General linear model

Parameter type

Treatment difference

Point estimate

10.4

Confidence interval

level

95%

sides

2-sided

lower limit

6.8

upper limit

Notes
[29] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariates.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[30]

Method

General linear model

Parameter type

Treatment difference

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.9

upper limit

13.3

Notes
[30] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariates.

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: DB Period

Top of page

End point title

Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: DB Period ^[31]

End point description

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the psychological well-being scale. This consisted of 10 items with 4 possible answers for each: 1 (Definitely disagree), 2 (Somewhat disagree), 3 (Somewhat agree) and 4 (Definitely agree). The least squares mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (worst) to 100 (best) using a conversion table. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Days 8, 29, 57 and 85 (Cycle 1).

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Scores on a Scale
least squares mean (standard error)
Day 8 (n=124; n=62)	6.6 ( 2.19 )	-2.7 ( 2.46 )
Day 29 (n=123; n=60)	4.5 ( 2.39 )	-6.9 ( 2.66 )
Day 57 (n=121; n=59)	6.1 ( 2.41 )	-5.1 ( 2.69 )
Day 85 (n=122; n=59)	0.7 ( 2.28 )	-7.5 ( 2.57 )

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[32]

Method

General linear model

Parameter type

Treatment difference

Point estimate

9.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

13.6

Notes
[32] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 29 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[33]

Method

General linear model

Parameter type

Treatment difference

Point estimate

11.4

Confidence interval

level

95%

sides

2-sided

lower limit

6.7

upper limit

Notes
[33] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[34]

Method

General linear model

Parameter type

Treatment difference

Point estimate

11.2

Confidence interval

level

95%

sides

2-sided

lower limit

6.4

upper limit

15.9

Notes
[34] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004 ^[35]

Method

General linear model

Parameter type

Treatment difference

Point estimate

8.1

Confidence interval

level

95%

sides

2-sided

lower limit

3.7

upper limit

12.6

Notes
[35] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period

Top of page

End point title

Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period ^[36]

End point description

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the aging appearance appraisal VAS. The VAS ranged from -15 ('I look 15 years younger') to +15 ('I look 15 years older'), with 0 indicating 'I look my age'. Subjects were asked to circle one number on the VAS indicating how many years younger or older they thought they looked compared to their actual age, with lower scores indicating a better outcome and higher scores a worse outcome. The least squares mean change from baseline at post-treatment visits is presented. Results are presented for the mITT population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Days 8, 29, 57 and 85 (Cycle 1).

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the DB period only and the arm 'BTX-A-HAC Solution 50 U - LT Analyses' represents the OL period.

End point values	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period
Number of subjects analysed	125	63
Units: Scores on a Scale
least squares mean (standard error)
Day 8 (n=123; n=62)	-0.8 ( 0.25 )	-0.2 ( 0.28 )
Day 29 (n=122; n=60)	-0.8 ( 0.28 )	0.3 ( 0.32 )
Day 57 (n=121; n=59)	-0.6 ( 0.34 )	0.7 ( 0.39 )
Day 85 (n=122; n=59)	-0.4 ( 0.31 )	1.1 ( 0.36 )

BTX-A-HAC vs Placebo: Day 8

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 8 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0174 ^[37]

Method

General linear model

Parameter type

Treatment difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

-0.1

Notes
[37] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

BTX-A-HAC vs Placebo: Day 29

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 29 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[38]

Method

General linear model

Parameter type

Treatment difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

-0.6

Notes
[38] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

BTX-A-HAC vs Placebo: Day 57

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 57 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[39]

Method

General linear model

Parameter type

Treatment difference

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

-0.7

Notes
[39] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

BTX-A-HAC vs Placebo: Day 85

Statistical analysis description

Treatment difference (BTX-A-HAC Solution – Placebo) at Day 85 Cycle 1.

Comparison groups

BTX-A-HAC Solution 50 U - DB Period v Placebo - DB Period

Number of subjects included in analysis

188

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[40]

Method

General linear model

Parameter type

Treatment difference

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

-0.8

Notes
[40] - The general linear model included mean change from baseline as a dependent variable and treatment group, gender and centre as fixed effects, and baseline severity score on ILA at maximum frown as covariate.

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses

Top of page

End point title

The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses ^[41]

End point description

The appearance of glabellar lines at maximum frown was assessed in the OL period at post-treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders at each post-treatment visit for Cycles 1 to 5 are presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period. The LTA population consisted of all subjects who received at least one injection of BTX-A-HAC solution in the OL period.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Percentage of Responders
number (confidence interval 95%)
Cycle 1: Day 8 (n=589)	75.7 (72.3 to 79.2)
Cycle 1: Day 29 (n=585)	82.2 (79.1 to 85.3)
Cycle 1: Day 57 (n=575)	69.9 (66.2 to 73.7)
Cycle 1: Day 85 (n=579)	53.0 (49.0 to 57.1)
Cycle 2: Day 8 (n=553)	80.8 (77.6 to 84.1)
Cycle 2: Day 29 (n=547)	84.5 (81.4 to 87.5)
Cycle 2: Day 57 (n=544)	74.3 (70.6 to 77.9)
Cycle 2: Day 85 (n=544)	53.7 (49.5 to 57.9)
Cycle 3: Day 8 (n=483)	86.5 (83.5 to 89.6)
Cycle 3: Day 29 (n=476)	87.8 (84.9 to 90.8)
Cycle 3: Day 57 (n=472)	78.6 (74.9 to 82.3)
Cycle 3: Day 85 (n=472)	56.8 (52.3 to 61.2)
Cycle 4: Day 8 (n=312)	84.3 (80.3 to 88.3)
Cycle 4: Day 29 (n=310)	86.1 (82.3 to 90.0)
Cycle 4: Day 57 (n=306)	76.1 (71.4 to 80.9)
Cycle 4: Day 85 (n=302)	50.7 (45.0 to 56.3)
Cycle 5: Day 8 (n=88)	84.1 (76.4 to 91.7)
Cycle 5: Day 29 (n=87)	82.8 (74.8 to 90.7)
Cycle 5: Day 57 (n=86)	55.8 (45.3 to 66.3)
Cycle 5: Day 85 (n=86)	45.3 (34.8 to 55.9)

No statistical analyses for this end point

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Rest: LT Analyses

Top of page

End point title

The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Rest: LT Analyses ^[42]

End point description

The appearance of glabellar lines at rest was assessed in the OL period at post-treatment follow-up visits using the ILA, a validated 4-point photographic scale of glabellar line severity. A responder was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders at each post-treatment visit for Cycles 1 to 5 are presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period. Results are presented for the LTA population. Only subjects with data available at the timepoints of testing are presented.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Percentage of Responders
number (confidence interval 95%)
Cycle 1: Day 8 (n=375)	74.1 (69.7 to 78.6)
Cycle 1: Day 29 (n=372)	81.7 (77.8 to 85.6)
Cycle 1: Day 57 (n=365)	77.3 (73.0 to 81.6)
Cycle 1: Day 85 (n=368)	61.1 (56.2 to 66.1)
Cycle 2: Day 8 (n=239)	74.5 (68.9 to 80.0)
Cycle 2: Day 29 (n=236)	78.4 (73.1 to 83.6)
Cycle 2: Day 57 (n=234)	71.4 (65.6 to 77.2)
Cycle 2: Day 85 (n=234)	47.9 (41.5 to 54.3)
Cycle 3: Day 8 (n=202)	82.2 (76.9 to 87.5)
Cycle 3: Day 29 (n=196)	84.2 (79.1 to 89.3)
Cycle 3: Day 57 (n=195)	80.0 (74.4 to 85.6)
Cycle 3: Day 85 (n=196)	58.7 (51.8 to 65.6)
Cycle 4: Day 8 (n=134)	77.6 (70.6 to 84.7)
Cycle 4: Day 29 (n=134)	81.3 (74.7 to 87.9)
Cycle 4: Day 57 (n=133)	78.9 (72.0 to 85.9)
Cycle 4: Day 85 (n=131)	59.5 (51.1 to 67.9)
Cycle 5: Day 8 (n=42)	85.7 (75.1 to 96.3)
Cycle 5: Day 29 (n=41)	78.0 (65.4 to 90.7)
Cycle 5: Day 57 (n=41)	63.4 (48.7 to 78.2)
Cycle 5: Day 85 (n=41)	56.1 (40.9 to 71.3)

No statistical analyses for this end point

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses

Top of page

End point title

The Percentage of Responders at Each Post-Treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses ^[43]

End point description

The appearance of glabellar lines at maximum frown was assessed using the SSA, a validated 4-point categorical scale of glabellar line severity, in the OL period at post-treatment follow-up visits. A responder was defined as having a severity grade of no wrinkles (Grade 0) or mild wrinkles (Grade 1) at maximum frown at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) wrinkles at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders at each post-treatment visit for Cycles 1 to 5 are presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period. Results are presented for the LTA population.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Percentage of Responders
number (confidence interval 95%)
Cycle 1: Day 8 (n=589)	62.8 (58.9 to 66.7)
Cycle 1: Day 29 (n=585)	72.5 (68.9 to 76.1)
Cycle 1: Day 57 (n=575)	64.3 (60.4 to 68.3)
Cycle 1: Day 85 (n=578)	43.6 (39.6 to 47.6)
Cycle 2: Day 8 (n=524)	74.8 (71.1 to 78.5)
Cycle 2: Day 29 (n=522)	75.3 (71.6 to 79.0)
Cycle 2: Day 57 (n=518)	69.3 (65.3 to 73.3)
Cycle 2: Day 85 (n=517)	44.3 (40.0 to 48.6)
Cycle 3: Day 8 (n=476)	78.8 (75.1 to 82.5)
Cycle 3: Day 29 (n=469)	80.6 (77.0 to 84.2)
Cycle 3: Day 57 (n=465)	67.1 (62.8 to 71.4)
Cycle 3: Day 85 (n=465)	44.9 (40.4 to 49.5)
Cycle 4: Day 8 (n=310)	80.3 (75.9 to 84.7)
Cycle 4: Day 29 (n=307)	75.2 (70.4 to 80.1)
Cycle 4: Day 57 (n=304)	66.1 (60.8 to 71.4)
Cycle 4: Day 85 (n=300)	47.3 (41.7 to 53.0)
Cycle 5: Day 8 (n=87)	66.7 (56.8 to 76.6)
Cycle 5: Day 29 (n=86)	62.8 (52.6 to 73.0)
Cycle 5: Day 57 (n=85)	49.4 (38.8 to 60.0)
Cycle 5: Day 85 (n=85)	37.6 (27.3 to 47.9)

No statistical analyses for this end point

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: LT Analyses

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End point title

The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: LT Analyses ^[44]

End point description

The subject's level of satisfaction with the appearance of their glabellar lines was assessed in the OL period at post-treatment follow-up visits of each treatment cycle using a 4-point categorical scale. A responder was defined as having a satisfaction rating of very satisfied (Grade 0) or satisfied (Grade 1) at a given visit and a satisfaction rating of dissatisfied (Grade 2) or very dissatisfied (Grade 3) at baseline. The cycle baseline was defined as the last measurement collected prior to the study treatment injection of the corresponding cycle. The percentage of responders at each post-treatment visit for Cycles 1 to 5 are presented. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period. Results are presented for the LTA population.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 - 5 (up to 15 months).

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Percentage of Responders
number (confidence interval 95%)
Cycle 1: Day 8 (n=589)	78.8 (75.5 to 82.1)
Cycle 1: Day 29 (n=585)	86.0 (83.2 to 88.8)
Cycle 1: Day 57 (n=575)	75.8 (72.3 to 79.3)
Cycle 1: Day 85 (n=579)	56.3 (52.3 to 60.3)
Cycle 2: Day 8 (n=448)	80.8 (77.2 to 84.5)
Cycle 2: Day 29 (n=446)	85.2 (81.9 to 88.5)
Cycle 2: Day 57 (n=442)	79.0 (75.2 to 82.8)
Cycle 2: Day 85 (n=444)	51.8 (47.2 to 56.4)
Cycle 3: Day 8 (n=401)	88.3 (85.1 to 91.4)
Cycle 3: Day 29 (n=395)	87.8 (84.6 to 91.1)
Cycle 3: Day 57 (n=391)	80.6 (76.6 to 84.5)
Cycle 3: Day 85 (n=392)	54.6 (49.7 to 59.5)
Cycle 4: Day 8 (n=263)	87.1 (83.0 to 91.1)
Cycle 4: Day 29 (n=260)	87.3 (83.3 to 91.4)
Cycle 4: Day 57 (n=257)	74.3 (69.0 to 79.7)
Cycle 4: Day 85 (n=254)	58.3 (52.2 to 64.3)
Cycle 5: Day 8 (n=73)	74.0 (63.9 to 84.0)
Cycle 5: Day 29 (n=72)	72.2 (61.9 to 82.6)
Cycle 5: Day 57 (n=71)	60.6 (49.2 to 71.9)
Cycle 5: Day 85 (n=70)	44.3 (32.6 to 55.9)

No statistical analyses for this end point

Secondary: Median Time to Retreatment in LT Analysis

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End point title

Median Time to Retreatment in LT Analysis ^[45]

End point description

The median time to onset of the next eligible treatment cycle is presented for Cycles 1 to 4. Cycle 1 corresponds to the first administration of BTX-A-HAC solution and includes the DB Cycle 1 of subjects who were treated with BTX-A-HAC solution, the Cycle 1 of de novo subjects and Cycle 2 of subjects who were randomised to receive placebo in the DB period. Subjects who were not subsequently retreated after a given cycle were excluded from the summary of time to retreatment at that cycle. Results are presented for the LTA population.

End point type

Secondary

End point timeframe

Cycles 1 - 4 (up to 12 months).

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Days
median (confidence interval 95%)
Cycle 1	113.0 (113.0 to 116.0)
Cycle 2 (n=558)	114.0 (113.0 to 117.0)
Cycle 3 (n=486)	110.0 (106.0 to 113.0)
Cycle 4 (n=305)	99.0 (92.0 to 110.0)

No statistical analyses for this end point

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: LT Analyses

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End point title

Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: LT Analyses ^[46]

End point description

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the satisfaction with facial appearance overall scale. This consisted of 10 items with 4 possible answers for each: 1 (Very Dissatisfied), 2 (Somewhat Dissatisfied), 3 (Somewhat Satisfied) and 4 (Very Satisfied). The mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (most dissatisfied) to 100 (most satisfied) using a conversion table. Results are presented for the LTA population.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 to 3; Days 8, 29 and 85 of Cycles 4 and 5.

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Scores on a Scale
arithmetic mean (standard deviation)
Cycle 1: Day 8 (n=586)	9.2 ( 14.5 )
Cycle 1: Day 29 (n=583)	10.9 ( 15.9 )
Cycle 1: Day 57 (n=517)	9.9 ( 15.4 )
Cycle 1: Day 85 (n=577)	6.6 ( 14.7 )
Cycle 2: Day 8 (n=553)	9.5 ( 14.6 )
Cycle 2: Day 29 (n=546)	9.7 ( 15.1 )
Cycle 2: Day 57 (n=1)	0.0 ( 0.0 )
Cycle 2: Day 85 (n=542)	4.8 ( 12.3 )
Cycle 3: Day 8 (n=484)	10.9 ( 15.0 )
Cycle 3: Day 29 (n=477)	9.9 ( 15.1 )
Cycle 3: Day 57 (n=3)	6.0 ( 4.6 )
Cycle 3: Day 85 (n=474)	5.0 ( 12.7 )
Cycle 4: Day 8 (n=314)	11.2 ( 14.3 )
Cycle 4: Day 29 (n=311)	9.9 ( 13.8 )
Cycle 4: Day 85 (n=308)	5.6 ( 11.8 )
Cycle 5: Day 8 (n=88)	12.0 ( 18.2 )
Cycle 5: Day 29 (n=87)	9.4 ( 17.5 )
Cycle 5: Day 85 (n=85)	5.3 ( 10.6 )

No statistical analyses for this end point

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: LT Analyses

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End point title

Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: LT Analyses ^[47]

End point description

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the psychological well-being scale. This consisted of 10 items with 4 possible answers for each: 1 (Definitely disagree), 2 (Somewhat disagree), 3 (Somewhat agree) and 4 (Definitely agree). The mean change from baseline at post-treatment visits of Rasch transformed scores is presented. The Rasch transformed score was calculated by adding the 10 items (scored from 1 to 4) and converting the score to a scale from 0 (worst) to 100 (best) using a conversion table. Results are presented for the LTA population.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 to 3; Days 8, 29 and 85 of Cycles 4 and 5.

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Scores on a Scale
arithmetic mean (standard deviation)
Cycle 1: Day 8 (n=588)	6.7 ( 16.9 )
Cycle 1: Day 29 (n=584)	7.2 ( 19.2 )
Cycle 1: Day 57 (n=518)	5.5 ( 18.7 )
Cycle 1: Day 85 (n=578)	2.7 ( 16.9 )
Cycle 2: Day 8 (n=553)	7.8 ( 14.0 )
Cycle 2: Day 29 (n=546)	8.2 ( 15.6 )
Cycle 2: Day 57 (n=1)	0.0 ( 0.0 )
Cycle 2: Day 85 (n=541)	4.6 ( 13.6 )
Cycle 3: Day 8 (n=484)	8.8 ( 15.5 )
Cycle 3: Day 29 (n=477)	9.4 ( 15.3 )
Cycle 3: Day 85 (n=474)	4.4 ( 13.0 )
Cycle 4: Day 8 (n=314)	10.1 ( 16.0 )
Cycle 4: Day 29 (n=309)	8.8 ( 14.9 )
Cycle 4: Day 85 (n=307)	6.3 ( 13.7 )
Cycle 5: Day 8 (n=88)	10.1 ( 17.0 )
Cycle 5: Day 29 (n=87)	8.4 ( 14.4 )
Cycle 5: Day 85 (n=86)	7.0 ( 12.1 )

No statistical analyses for this end point

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses

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End point title

Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses ^[48]

End point description

FACE-Q is a subject-reported outcome instrument to evaluate the experience and outcomes of aesthetic facial procedures from the subject's perspective. One of three scales that was selected for this study was the aging appearance appraisal VAS. The VAS ranged from -15 ('I look 15 years younger') to +15 ('I look 15 years older'), with 0 indicating 'I look my age'. Subjects were asked to circle one number on the VAS indicating how many years younger or older they thought they looked compared to their actual age, with lower scores indicating a better outcome and higher scores a worse outcome. The mean change from baseline at post-treatment visits is presented. Results are presented for the LTA population.

End point type

Secondary

End point timeframe

Days 8, 29, 57 and 85 of Cycles 1 to 3; Days 8, 29 and 85 of Cycles 4 and 5.

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point presents data for the OL period only and the arms 'BTX-A-HAC Solution 50 U - DB Period' and 'Placebo - DB Period' represent the DB period.

End point values	BTX-A-HAC Solution 50 U - LT Analyses
Number of subjects analysed	595
Units: Scores on a Scale
arithmetic mean (standard deviation)
Cycle 1: Day 8 (n=586)	-1.0 ( 2.2 )
Cycle 1: Day 29 (n=583)	-1.3 ( 2.5 )
Cycle 1: Day 57 (n=518)	-1.2 ( 2.6 )
Cycle 1: Day 85 (n=578)	-0.8 ( 2.5 )
Cycle 2: Day 8 (n=553)	-0.9 ( 1.8 )
Cycle 2: Day 29 (n=546)	-1.0 ( 1.9 )
Cycle 2: Day 57 (n=1)	0.0 ( 0.0 )
Cycle 3: Day 8 (n=484)	-1.0 ( 1.9 )
Cycle 3: Day 29 (n=477)	-1.0 ( 2.1 )
Cycle 3: Day 57 (n=3)	-0.3 ( 1.5 )
Cycle 3: Day 85 (n=474)	-0.5 ( 1.7 )
Cycle 4: Day 8 (n=314)	-1.1 ( 1.8 )
Cycle 4: Day 29 (n=311)	-0.9 ( 1.8 )
Cycle 4: Day 85 (n=307)	-0.5 ( 1.6 )
Cycle 5: Day 8 (n=88)	-1.3 ( 2.3 )
Cycle 5: Day 29 (n=87)	-1.1 ( 2.0 )
Cycle 5: Day 85 (n=86)	-0.7 ( 1.9 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment emergent adverse events were collected from baseline (Day 1 Cycle 1 of DB period/OL period, as applicable) up to end of DB period (for DB period arms) or up to end of Cycle 5 of the OL period (for LT Analyses arm), up to approximately 20 months.

Adverse event reporting additional description

DB period arms: the safety population for the DB period consisted of all subjects who received at least one injection of study treatment into at least one injection site. LT Analyses arm: the LTA population included all subjects included in the DB period/de novo subjects who received at least one injection of BTX-A-HAC solution in the OL period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

BTX-A-HAC Solution 50 U - DB Period

Reporting group description

Reporting group title

Placebo - DB Period

Reporting group description

Reporting group title

BTX-A-HAC Solution 50 U - LT Analyses

Reporting group description

Serious adverse events	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period	BTX-A-HAC Solution 50 U - LT Analyses
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 126 (0.79%)	2 / 64 (3.13%)	34 / 595 (5.71%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myxofibrosarcoma
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestine carcinoma
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Catheter site extravasation
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
alternative dictionary used: MedDRA 19.0
subjects affected / exposed	0 / 126 (0.00%)	1 / 64 (1.56%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Menorrhagia
alternative dictionary used: MedDRA 19.0
subjects affected / exposed	1 / 126 (0.79%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Post-traumatic stress disorder
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Tendon rupture
subjects affected / exposed	0 / 126 (0.00%)	1 / 64 (1.56%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	2 / 595 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Sciatica
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Holmes-Adie pupil
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Autoimmune pancreatitis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	2 / 595 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastrointestinal infection
alternative dictionary used: MedDRA 19.0
subjects affected / exposed	0 / 126 (0.00%)	1 / 64 (1.56%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngitis bacterial
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritoneal abscess
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	1 / 595 (0.17%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	BTX-A-HAC Solution 50 U - DB Period	Placebo - DB Period	BTX-A-HAC Solution 50 U - LT Analyses
Total subjects affected by non serious adverse events
subjects affected / exposed	35 / 126 (27.78%)	13 / 64 (20.31%)	279 / 595 (46.89%)
Vascular disorders
Haematoma
subjects affected / exposed	5 / 126 (3.97%)	0 / 64 (0.00%)	15 / 595 (2.52%)
occurrences all number	5	0	16
Nervous system disorders
Headache
subjects affected / exposed	13 / 126 (10.32%)	4 / 64 (6.25%)	117 / 595 (19.66%)
occurrences all number	22	4	272
Migraine
subjects affected / exposed	2 / 126 (1.59%)	0 / 64 (0.00%)	13 / 595 (2.18%)
occurrences all number	5	0	20
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	3 / 126 (2.38%)	0 / 64 (0.00%)	6 / 595 (1.01%)
occurrences all number	3	0	6
Eye disorders
Eyelid ptosis
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	15 / 595 (2.52%)
occurrences all number	0	0	19
Eyelid oedema
subjects affected / exposed	2 / 126 (1.59%)	0 / 64 (0.00%)	14 / 595 (2.35%)
occurrences all number	3	0	16
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 126 (1.59%)	1 / 64 (1.56%)	25 / 595 (4.20%)
occurrences all number	2	3	29
Infections and infestations
Nasopharyngitis
subjects affected / exposed	13 / 126 (10.32%)	8 / 64 (12.50%)	168 / 595 (28.24%)
occurrences all number	14	10	252
Pharyngitis
subjects affected / exposed	3 / 126 (2.38%)	0 / 64 (0.00%)	7 / 595 (1.18%)
occurrences all number	3	0	7
Bronchitis
subjects affected / exposed	1 / 126 (0.79%)	0 / 64 (0.00%)	20 / 595 (3.36%)
occurrences all number	1	0	21
Sinusitis
subjects affected / exposed	1 / 126 (0.79%)	1 / 64 (1.56%)	19 / 595 (3.19%)
occurrences all number	1	2	22
Gastroenteritis
subjects affected / exposed	1 / 126 (0.79%)	0 / 64 (0.00%)	18 / 595 (3.03%)
occurrences all number	1	0	19
Influenza
subjects affected / exposed	0 / 126 (0.00%)	0 / 64 (0.00%)	16 / 595 (2.69%)
occurrences all number	0	0	17
Cystitis
subjects affected / exposed	1 / 126 (0.79%)	0 / 64 (0.00%)	15 / 595 (2.52%)
occurrences all number	5	0	20

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The Percentage of Responders at Day 29 Cycle 1 as Measured by ILA of Glabellar Lines at Maximum Frown: DB Period

Primary: The Percentage of Responders at Day 29 Cycle 1 as Measured by ILA of Glabellar Lines at Maximum Frown: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit (Except Day 29 Cycle 1) as Measured by the ILA at Maximum Frown: DB Period

Secondary: The Percentage of Responders on Day 29 Cycle 1 Who Remained Responders on Days 57 and 85 as Measured by the ILA at Maximum Frown: DB Period

Secondary: The Percentage of Responders on Day 29 Cycle 1 Who Remained Responders on Days 57 and 85 as Measured by the ILA at Maximum Frown: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the ILA at Rest: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject's Self-Assessment (SSA) at Maximum Frown: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: DB Period

Secondary: The Median Time to Onset of Treatment Response Based on the Subject’s Diary Card: DB Period

Secondary: The Median Time to Onset of Treatment Response Based on the Subject’s Diary Card: DB Period

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: DB Period

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: DB Period

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: DB Period

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: DB Period

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal Visual Analogue Scale (VAS): DB Period

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Maximum Frown: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Rest: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the ILA at Rest: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit as Measured by the SSA at Maximum Frown: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: LT Analyses

Secondary: The Percentage of Responders at Each Post-Treatment Visit to the Study Centre as Measured by the Subject’s Level of Satisfaction with the Appearance of Their Glabellar Lines: LT Analyses

Secondary: Median Time to Retreatment in LT Analysis

Secondary: Median Time to Retreatment in LT Analysis

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: LT Analyses

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Satisfaction with Facial Appearance Overall Scale: LT Analyses

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: LT Analyses

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Psychological Well-Being Scale: LT Analyses

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses

Secondary: Change from Baseline at All Post-Treatment Visits in the FACE-Q Aging Appearance Appraisal VAS: LT Analyses

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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